seizure disorder jeffrey t. reisert, do university of new england physician assistant program 27 aug...
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Seizure DisorderSeizure Disorder
Jeffrey T. Reisert, DOJeffrey T. Reisert, DOUniversity of New EnglandUniversity of New England
Physician Assistant ProgramPhysician Assistant Program27 AUG 200927 AUG 2009
Contact InformationContact Information
Jeffrey T. Reisert, DOJeffrey T. Reisert, DO
[email protected]@Hitchcock.org
Tenney Mountain Internal MedicineTenney Mountain Internal Medicine
251 Mayhew Turnpike251 Mayhew Turnpike
Plymouth, NH 03264Plymouth, NH 03264
(603) 536-6355(603) 536-6355
(603) 536-6356 (fax)(603) 536-6356 (fax)
ObjectivesObjectives
Define different patterns of seizuresDefine different patterns of seizuresRecognize symptoms of seizureRecognize symptoms of seizureBe able to differentiate types of Be able to differentiate types of
common seizures/patterns in children common seizures/patterns in children and adultsand adults
Recognize treatments of acute Recognize treatments of acute seizure, status epilepticus, and seizure, status epilepticus, and prevention of seizuresprevention of seizures
Illustrative CaseIllustrative Case
You are covering the ED when a 40 You are covering the ED when a 40 year old male presents by year old male presents by ambulance, reportedly for “Loss of ambulance, reportedly for “Loss of consciousness”consciousness”
You interview a sleepy patient and You interview a sleepy patient and interview their friend.interview their friend.
The patient works as a carpenter for The patient works as a carpenter for a home construction firm. His history a home construction firm. His history is benign.is benign.
What questions do you have?What questions do you have?
Important factsImportant facts
The patient was at the job site and The patient was at the job site and stated he didn’t feel well. His co-stated he didn’t feel well. His co-worker informs you he collapsed worker informs you he collapsed after saying he didn’t feel well.after saying he didn’t feel well.
He was noted to have “eyes that He was noted to have “eyes that rolled back in his head” and rolled back in his head” and drewling.drewling.
Then he tensed up and began Then he tensed up and began shaking for “a long time.”shaking for “a long time.”
What is your differential What is your differential diagnosis?diagnosis?
SeizureSeizureCardiac eventCardiac eventAlcohol withdrawal?Alcohol withdrawal?
Definition of Seizure DisorderDefinition of Seizure Disorder
Harrison’s Principles of Internal Medicine Harrison’s Principles of Internal Medicine defines a seizure as a paroxysmal event due defines a seizure as a paroxysmal event due to abnormal CNS discharge with resultant to abnormal CNS discharge with resultant manifestations depending on area involved.manifestations depending on area involved.
5-10% of population in lifetime have a 5-10% of population in lifetime have a seizureseizure
More prevalent in early childhood and later More prevalent in early childhood and later in adulthoodin adulthood
Epilepsy defines a patient with recurrent Epilepsy defines a patient with recurrent seizures (not a single seizure).seizures (not a single seizure). About 0.3-0.5% of populationAbout 0.3-0.5% of population
Types of seizuresTypes of seizures
International League Against International League Against Epilepsy (ILAE)-1981Epilepsy (ILAE)-1981
International classification of International classification of epileptic seizuresepileptic seizures
Table 348.1Table 348.1
Two basic types of seizuresTwo basic types of seizures
PartialPartialDeranged area of cerebral cortex often Deranged area of cerebral cortex often
due to a structural anomaly-due to a structural anomaly-Consciousness is preservedConsciousness is preserved
Further divided in to simple partial and Further divided in to simple partial and complex partial-Consciousness is complex partial-Consciousness is impairedimpaired
Third where partial seizures secondarily Third where partial seizures secondarily generalizedgeneralized
Generalized-Next slideGeneralized-Next slide
GeneralizedGeneralized
Diffuse region of brain firing Diffuse region of brain firing simultaneouslysimultaneously
Often due a widespread problemOften due a widespread problemCellular disorder (i.e.: mental Cellular disorder (i.e.: mental
retardation)retardation)Biochemical disruption (i.e.: low sodium)Biochemical disruption (i.e.: low sodium)Structural issue (i.e.: brain tumor)Structural issue (i.e.: brain tumor)
Simple Partial SeizuresSimple Partial Seizures
May be motor, sensory, autonomic, May be motor, sensory, autonomic, psychic but without loss of psychic but without loss of consciousness (LOC)consciousness (LOC)
Example: May get a hand tremor on Example: May get a hand tremor on opposite side of abnormal brain opposite side of abnormal brain activityactivity
Often clonic with repetitive Often clonic with repetitive flexion/extensionflexion/extension
EEG: Abnormal impulses in focal area EEG: Abnormal impulses in focal area of brainof brain
Variations of simple partial Variations of simple partial seizuresseizures
Jacksonian MarchJacksonian MarchMotor activity begins distally, like Motor activity begins distally, like
fingers, and spreads to whole extremityfingers, and spreads to whole extremityEEG: spike wavesEEG: spike waves
Todd’s paralysisTodd’s paralysisLocal paresis lasting minutes to hoursLocal paresis lasting minutes to hours
Epilepsia partialis continuaEpilepsia partialis continuaContinues hours to daysContinues hours to days
Additional symptoms in simple Additional symptoms in simple partial seizurespartial seizures
Changes in somatic sensations Changes in somatic sensations (paresthesias)(paresthesias)
Change in vision (flashing lights, Change in vision (flashing lights, hallucinations)hallucinations)
Changes in equilibrium (falling, Changes in equilibrium (falling, vertigo)vertigo)
Autonomic changes (flushing, Autonomic changes (flushing, sweating)sweating)
Odd feelings (déjà vu)Odd feelings (déjà vu)
Complex Partial SeizuresComplex Partial Seizures Focal activity progresses to loss of contact with Focal activity progresses to loss of contact with
environment (ictal stage)environment (ictal stage) StareStare Amnesia – may forget what happenedAmnesia – may forget what happened
Often begins with an aura stereotypical for the Often begins with an aura stereotypical for the patient……Feel funny.patient……Feel funny.
Followed by ictal stageFollowed by ictal stage Involuntary behaviorsInvoluntary behaviors Chewing, pickingChewing, picking
Post ictal confusionPost ictal confusion Lasts seconds to hoursLasts seconds to hours EEG between spells (inter ictal) usually normal (or EEG between spells (inter ictal) usually normal (or
may show brief discharge of spikes (sharp waves)may show brief discharge of spikes (sharp waves)
Partial seizures with secondary Partial seizures with secondary generalizationgeneralization
Electrical discharge spread and both Electrical discharge spread and both hemispheres become involvedhemispheres become involved
Results in tonic-clonic seizureResults in tonic-clonic seizureCommon when partial seizures in Common when partial seizures in
frontal lobefrontal lobeLook like generalized seizuresLook like generalized seizures
Generalized seizuresGeneralized seizures
Arise in both cerebral hemispheres Arise in both cerebral hemispheres simultaneouslysimultaneously
Look like focal seizure that Look like focal seizure that secondarily generalized though not secondarily generalized though not associated with a specific focal onset associated with a specific focal onset eventevent
Includes absence seizures and tonic-Includes absence seizures and tonic-clonic seizuresclonic seizures
Absence Seizures (Petit mal)Absence Seizures (Petit mal)
Brief LOC without postural control.Brief LOC without postural control.Usually last a few secondsUsually last a few secondsNo post ictal confusionNo post ictal confusionMay have other subtle findingsMay have other subtle findings
Eye blinkingEye blinkingChewingChewingClonic movement of handsClonic movement of hands
Absence seizures cont.Absence seizures cont.
Onset typically in childhood, 4-8 y/o Onset typically in childhood, 4-8 y/o or early adolescenceor early adolescence
Makes up 15-20% of childhood Makes up 15-20% of childhood seizuresseizures
May occur all day May occur all day long…..Daydreaming appearancelong…..Daydreaming appearance
Absence seizures cont.Absence seizures cont.
EEGEEGGeneralized symmetrical dischargeGeneralized symmetrical dischargeSpike and waveSpike and waveStart stop with inter-ictal normal EEGStart stop with inter-ictal normal EEGWorsen with hyperventilation maneuverWorsen with hyperventilation maneuver
May be associated with T-C seizuresMay be associated with T-C seizures60-70% of cases remiss in childhood60-70% of cases remiss in childhood
Atypical absence seizuresAtypical absence seizures
Similar to absence but symptoms last Similar to absence but symptoms last longerlonger
More motor featuresMore motor featuresMay have a brain abnormality such May have a brain abnormality such
as mental retardation/developmental as mental retardation/developmental delaydelay
Harder to tx than ordinary absence Harder to tx than ordinary absence seizuresseizures
Generalized Tonic-Clonic Generalized Tonic-Clonic SeizuresSeizures
10% of patients with epilepsy10% of patients with epilepsyAre the most common type when Are the most common type when
seizures are due to metabolic seizures are due to metabolic derangementderangement
Episodes are of sudden onsetEpisodes are of sudden onsetMay have prodrome but less so than May have prodrome but less so than
aura in focal seizures that secondarily aura in focal seizures that secondarily generalizegeneralize
T-C Seizures-CharacteristicsT-C Seizures-Characteristics
Tonic phaseTonic phase Increased muscle toneIncreased muscle tone
Often a moan or cryOften a moan or cry Change in respirationChange in respiration
Secretions poolSecretions pool CyanosisCyanosis Jaw clenches, bite tongueJaw clenches, bite tongue
Sympathetic symptomsSympathetic symptoms Increased BP, HRIncreased BP, HR Pupil dilationPupil dilation
T-C Seizure Features cont.T-C Seizure Features cont. Clonic activityClonic activity
Muscles relax and contractMuscles relax and contract Usually lasts about a minuteUsually lasts about a minute
Post-ictal statePost-ictal state UnresponsiveUnresponsive FlaccidFlaccid Salivation or airway obstructionSalivation or airway obstruction Bowel or bladder incontinenceBowel or bladder incontinence
Seizures may last minutes to hours before Seizures may last minutes to hours before awakeningawakening
Post seizurePost seizure HeadacheHeadache FatigueFatigue Muscle achesMuscle aches
T-C Seizures-EEGT-C Seizures-EEG
Tonic phaseTonic phaseIncreased low voltage fast activityIncreased low voltage fast activityHigh amplitude polyspike dischargesHigh amplitude polyspike discharges
Clonic phaseClonic phaseSpike and wave activity developsSpike and wave activity develops
Post ictalPost ictalSlowing then recoverySlowing then recovery
T-C Seizures-VariationsT-C Seizures-Variations
Atonic seizuresAtonic seizures 1-2 seconds lose motor tone1-2 seconds lose motor tone Brief loss of consciousness (LOC)Brief loss of consciousness (LOC) No post-ictal confusionNo post-ictal confusion Risk after head injuryRisk after head injury Also associated with other epileptic syndromesAlso associated with other epileptic syndromes
Myoclonic seizuresMyoclonic seizures Brief contraction or jerkBrief contraction or jerk Like when you fall asleep and you twitchLike when you fall asleep and you twitch Seen in brain injuriesSeen in brain injuries
Other Generalized Seizure Other Generalized Seizure categoriescategories
Juvenile myoclonic epilepsyJuvenile myoclonic epilepsyLennox Gastaut syndromeLennox Gastaut syndromeMesial temporal lobe epilepsyMesial temporal lobe epilepsy
Juvenile Myoclonic epilepsyJuvenile Myoclonic epilepsy
AdolescenceAdolescenceBilateral jerk with maintained Bilateral jerk with maintained
consciousnessconsciousnessWorse with awakening, sleep deprivationWorse with awakening, sleep deprivationBenignBenign
Good response to medsGood response to medsMay spontaneously remitMay spontaneously remit
Associated with other epileptic Associated with other epileptic syndromessyndromes
Lennox Gastaut syndromeLennox Gastaut syndrome
Seen in childrenSeen in children Multiple seizure typesMultiple seizure types EEG slowing and spike wavesEEG slowing and spike waves Usually impaired cognitive functionUsually impaired cognitive function Associated with central nervous system Associated with central nervous system
(CNS) disease(CNS) disease Developmental delayDevelopmental delay TraumaTrauma InfectionInfection Neural injuriesNeural injuries
Often difficult to controlOften difficult to control
Mesial temporal lobe epilepsyMesial temporal lobe epilepsy
Difficult to controlDifficult to controlPartial epilepsy with characteristic Partial epilepsy with characteristic
featuresfeaturesMRI shows hippocampal sclerosisMRI shows hippocampal sclerosis
Seizures-EtiologySeizures-Etiology
Harrison’s: Shift in balance of Harrison’s: Shift in balance of excitation and inhibition in CNSexcitation and inhibition in CNS
MechanismsMechanismsChange in seizure threshold (i.e.: Fevers Change in seizure threshold (i.e.: Fevers
in children)in children)Genetic roleGenetic roleTraumatic brain injuryTraumatic brain injuryOther events (strokes, infection)Other events (strokes, infection)Precipitating factorsPrecipitating factors
Seizure causes cont.Seizure causes cont.
Precipitating factorsPrecipitating factorsStressStressSleep deprivationSleep deprivationMensesMensesMedicationsMedicationsEtc.Etc.
May take years to develop after May take years to develop after eventevent
What happens?What happens?
A burst of electrical activityA burst of electrical activity Influx of extracellular calciumInflux of extracellular calcium
Excitatory molecules such as NMDA (N-methyl-D-Excitatory molecules such as NMDA (N-methyl-D-aspartate) may further calcium influxaspartate) may further calcium influx
Influx of sodiumInflux of sodium Under influence of GABA (Gamma-aminobutyric acid) or Under influence of GABA (Gamma-aminobutyric acid) or
potassium channelspotassium channels Spike dischargeSpike discharge Inhibitory neurons overwhelmed by calcium and Inhibitory neurons overwhelmed by calcium and
potassiumpotassium Propagation of action potentialsPropagation of action potentials Channel problems may be source of genetic Channel problems may be source of genetic
epilepsyepilepsy
Seizures, age basisSeizures, age basis
Table 348-4Table 348-4NeonatesNeonates
Birth injury, hypoxemiaBirth injury, hypoxemiaCongenital abnormalitiesCongenital abnormalitiesDrugs (maternal)Drugs (maternal)
Early ChildhoodEarly ChildhoodFebrile seizuresFebrile seizures
Febrile SeizuresFebrile Seizures 3-5% of children3-5% of children Most occur from 3mo to 5ysMost occur from 3mo to 5ys
Most 18-24 moMost 18-24 mo Infection typesInfection types
Otitis mediaOtitis media Respiratory infectionRespiratory infection GastroenteritisGastroenteritis
PresentationPresentation Early on in febrile illness T-C activityEarly on in febrile illness T-C activity
Recurrence about 1/3 of ptsRecurrence about 1/3 of pts Can be a simple febrile seizure (one event) or Can be a simple febrile seizure (one event) or
complex febrile seizure (repeated activity)complex febrile seizure (repeated activity) Not epilepsyNot epilepsy
Age cont.Age cont.
ChildhoodChildhood Usually when epilepsy becomes apparentUsually when epilepsy becomes apparent
AdolescenceAdolescence Think traumaThink trauma The worse the trauma the worse the seizuresThe worse the trauma the worse the seizures
AdulthoodAdulthood Cerebrovascular disease (50% of new onset seizures in Cerebrovascular disease (50% of new onset seizures in
adults)adults) TraumaTrauma CNS tumorsCNS tumors Degenerative diseasesDegenerative diseases Medical (Hypo/hyperglycemia, renal failure, liver Medical (Hypo/hyperglycemia, renal failure, liver
disease, and drugsdisease, and drugs
Diagnosis seizure disorderDiagnosis seizure disorder
History is key (observer/bystander)History is key (observer/bystander) EEGEEG
ASAP to measure brain activityASAP to measure brain activityAwakeness/activityAwakeness/activity
Burst of action potentialsBurst of action potentials Baseline alpha wave (8-13 Hz) with eyes closedBaseline alpha wave (8-13 Hz) with eyes closed Faster beta activity (>13 Hz) increase with Faster beta activity (>13 Hz) increase with
activity/eye opening. Amount varies.activity/eye opening. Amount varies. Slower theta activity (4-7 Hz) and delta (<4 Hz)Slower theta activity (4-7 Hz) and delta (<4 Hz)
EEG Cont.EEG Cont.
Different situations are assessed (montages)Different situations are assessed (montages) Awake/asleepAwake/asleep Eyes open/closed or with photo stimulationEyes open/closed or with photo stimulation HyperventilationHyperventilation Sleep deprivationSleep deprivation
Key findingsKey findings Abnormal activity that starts/stops abruptly ORAbnormal activity that starts/stops abruptly OR Abnormal activity during T-C seizureAbnormal activity during T-C seizure Inter-ictal may see spikes or sharp waves in 40% Inter-ictal may see spikes or sharp waves in 40%
of cases (worse prognosis) – harder to treatof cases (worse prognosis) – harder to treat
Evaluation and WorkupEvaluation and Workup
EEGEEG ImagingImaging
Most getMost getMRI bestMRI best
Blood testsBlood testsUsually normal (not helpful)Usually normal (not helpful)May see elevated prolactin level in first May see elevated prolactin level in first
30 mins.30 mins.
Differential diagnosisDifferential diagnosis
Table 348-6Table 348-6 SyncopeSyncope
Tired, sweaty, tunnel visionTired, sweaty, tunnel vision May have 10 sec of convulsive activityMay have 10 sec of convulsive activity (Seizures may have aura, cyanosis, LOC, >30 sec. (Seizures may have aura, cyanosis, LOC, >30 sec.
activity, post-ictal disorientation, muscle soreness, or activity, post-ictal disorientation, muscle soreness, or sleepiness)sleepiness)
Psychogenic seizuresPsychogenic seizures Non-epileptiform behaviors that resemble seizuresNon-epileptiform behaviors that resemble seizures Seen with stress/conversion reactionSeen with stress/conversion reaction Head turning, shaking, twitching, no LOC, pelvic thrust Head turning, shaking, twitching, no LOC, pelvic thrust
that waxes and wanesthat waxes and wanes ? Video EEG? Video EEG
Overview of treatmentOverview of treatment Basic life supportBasic life support
Vital signs, CPRVital signs, CPR Treat cause if identifiedTreat cause if identified
Infection, tumor, drugsInfection, tumor, drugs Cerebrospinal fluid tap?Cerebrospinal fluid tap? Imaging (MRI preferred)Imaging (MRI preferred)
Meds if more than one episode or high riskMeds if more than one episode or high risk 31-71% risk of second seizure in one year31-71% risk of second seizure in one year
Assess for likelihood of recurrenceAssess for likelihood of recurrence Are meds needed long term?Are meds needed long term? 2 year trial on meds?2 year trial on meds?
SafetySafety WorkWork DrivingDriving
Seizure meds, overviewSeizure meds, overview
Right drug for certain type of seizureRight drug for certain type of seizureOne drug?One drug?Add slowlyAdd slowlyOlder meds first lineOlder meds first line
Phenytoin (DilantinPhenytoin (Dilantin®), valproic acid ®), valproic acid (Depakote®), carbamazepine (Depakote®), carbamazepine (Tegretol®)(Tegretol®)
Newer meds secondNewer meds second
Medications-Mechanism of Medications-Mechanism of ActionAction
Block activity of ion channels or neurotransmittersBlock activity of ion channels or neurotransmitters Inhibit Na+ dependent action potentialsInhibit Na+ dependent action potentials
Phenytoin, carbamazepine, lamotrigine (LamictalPhenytoin, carbamazepine, lamotrigine (Lamictal®), ®), topiramate (Topamax®), zonisamide (Zonegran®)topiramate (Topamax®), zonisamide (Zonegran®)
Inhibit Ca++ channelsInhibit Ca++ channels PhenytoinPhenytoin
Decrease glutamate releaseDecrease glutamate release LamotrigineLamotrigine
Increase GABA functionIncrease GABA function Benzodiazepines, phenobarbitalBenzodiazepines, phenobarbital
Increase GABA availabilityIncrease GABA availability Valproic acid, gabapentin (NeurontinValproic acid, gabapentin (Neurontin®), tiagabine (Gabitril®)®), tiagabine (Gabitril®)
Inhibit Ca++ channels in thalamus (absence seizures)Inhibit Ca++ channels in thalamus (absence seizures) Ethosuximide, valproic acidEthosuximide, valproic acid
Treatment by seizure typeTreatment by seizure type
Partial seizuresPartial seizures Carbamazepine (3-4 x per day, low WBC, bone Carbamazepine (3-4 x per day, low WBC, bone
marrow aplasia, hepatotox)marrow aplasia, hepatotox) Phenytoin (1-2 x per day, levels, tox, Phenytoin (1-2 x per day, levels, tox,
hirsuitism, coarse facial features, gingival hirsuitism, coarse facial features, gingival hyperplasia, affect on bone metabolism)hyperplasia, affect on bone metabolism)
Lamotrigine (Rash)Lamotrigine (Rash) Valproic acid (GI tox, bone marrow Valproic acid (GI tox, bone marrow
suppression, hepatotox)suppression, hepatotox) Generalized seizuresGeneralized seizures
Valproic acid, lamotrigine, carbamazepine, Valproic acid, lamotrigine, carbamazepine, phenytoinphenytoin
Medications-MonitoringMedications-Monitoring
Adverse drug reactionsAdverse drug reactionsEffectivenessEffectivenessLevelsLevelsLiver function testsLiver function testsBlood countsBlood countsDrugs in combo?Drugs in combo?
Stopping drugsStopping drugs
Consider ifConsider ifLow riskLow riskOne seizure then seizure freeOne seizure then seizure freeNormal exam (no developmental delay, Normal exam (no developmental delay,
head injury, etc.)head injury, etc.)Normal EEGNormal EEGDo slowlyDo slowly
Driving implications?Driving implications?
Status epilepticusStatus epilepticus
Continuous seizureContinuous seizure Some say if more than 15-30 minsSome say if more than 15-30 mins Others if > 15 secondsOthers if > 15 seconds May range from T-C seizure to more subtle May range from T-C seizure to more subtle
(finger or eye movement)(finger or eye movement) May need EEG to verifyMay need EEG to verify
Medical emergencyMedical emergency Cardiovascular implicationsCardiovascular implications HyperthermiaHyperthermia Metabolic derangementsMetabolic derangements CNS injuryCNS injury
Status epilepticus-CausesStatus epilepticus-Causes
Metabolic problemsMetabolic problemsDrug toxicityDrug toxicityCNS infection or tumorCNS infection or tumorHead injuryHead injuryRefractory epilepsyRefractory epilepsy
Status epilepticus-TreatmentStatus epilepticus-Treatment
Metabolic work upMetabolic work upBenzodiazepine (Lorazepam, Benzodiazepine (Lorazepam,
diazepam (Valiumdiazepam (Valium®), others®), othersPhenytoin – can burn armPhenytoin – can burn armPhenobarbitalPhenobarbitalAnesthesiaAnesthesia
Surgical treatment of Surgical treatment of seizuresseizures
Use is primarily in refractory epilepsyUse is primarily in refractory epilepsy ProceduresProcedures
Temporal lobectomyTemporal lobectomy Focal lesion removal (or more such as Focal lesion removal (or more such as
hemispherectomy)hemispherectomy) Corpus callosotomyCorpus callosotomy
RequiresRequires EEG, Video EEGEEG, Video EEG NeuroimagingNeuroimaging SPECT or PET scans (functional)SPECT or PET scans (functional) Electrical mappingElectrical mapping
Vagal nerve stimulatorVagal nerve stimulator
Place a bipolar electrode in L vagus Place a bipolar electrode in L vagus nervenerve
Generator delivers a pulseGenerator delivers a pulseMay take a while to workMay take a while to workMOA: May simply increase seizure MOA: May simply increase seizure
thresholdthreshold
Other issuesOther issues
Developmental delay/mental retardationDevelopmental delay/mental retardation ParentingParenting StigmaStigma 2-3x greater death rate2-3x greater death rate Work? Driving?Work? Driving? Menstrual cycles may increase riskMenstrual cycles may increase risk PregnancyPregnancy
Seizures may worsen or improve in half of ptsSeizures may worsen or improve in half of pts May alter drug levelsMay alter drug levels Tx may cause birth defectsTx may cause birth defects May affect contraceptionMay affect contraception
Case wrap upCase wrap up HistoryHistory
No prior eventNo prior event IncontinenceIncontinence Sudden onsetSudden onset ProdromeProdrome Tonic clonic activityTonic clonic activity
ExamExam Post ictal grogginessPost ictal grogginess Wet pantsWet pants
Work up?Work up? ImagingImaging EEGEEG Check glucose, chemistries, drug level?Check glucose, chemistries, drug level? Meds or observe?Meds or observe?
TreatmentTreatment Dilantin or similarDilantin or similar No driving/laddersNo driving/ladders
Questions?Questions?
ReferencesReferences
Harrison’sHarrison’sUp-To-DateUp-To-DateNetterNetter